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bioRxiv · 10.1101/2023.01.13.523980

Genome-wide CRISPR screen reveals genetic modifiers of Ca2+-mediated cell death

Reyes Gaido, O. E.·Schole, K. L.·Anderson, M. E.·Luczak, E. D.
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Abstract

Ca2+ is a fundamental determinant of survival in living cells. Excessive intracellular Ca2+ causes cellular toxicity and death but the genetic pathways contributing to Ca2+ induced cell death are incompletely understood. Here, we performed genome-wide CRISPR knock-out screening in human cells challenged with the Ca2+ ionophore ionomycin and identified genes and pathways essential for cell death after Ca2+ overload. We discovered 115 protective gene knockouts, 82 of which are non-essential genes and 21 of which belong to the druggable genome. Notably, members of store operated Ca2+ entry (SOCE), very long-chain fatty acid synthesis, and SWItch/Sucrose Non-Fermentable (SWI/SNF) pathways provided marked protection against Ca2+ toxicity. These results reveal pathways previously unknown to mediate Ca2+-induced cell death and provide a resource for the development of pharmacotherapies against the sequelae of Ca2+ overload in disease.

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Reyes Gaido, O. E., Schole, K. L., Anderson, M. E., Luczak, E. D.. 2023-01-14. Genome-wide CRISPR screen reveals genetic modifiers of Ca2+-mediated cell death. https://doi.org/10.1101/2023.01.13.523980

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